Telomere shortening may cause genetic anticipation in VHL syndrome

Genetic anticipation describes the situation where younger generations of a family with a genetic disease develop symptoms at a younger age, develop more severe symptoms, or both. A study earlier this year showed that there is evidence of genetic anticipation in the genetic kidney cancer syndrome Hereditary Leiomyomatosis and Renal Cell Cancer (HLRCC) (Wong et al., 2014), and more recently a study suggests that this phenomenon is also seen in another hereditary kidney cancer syndrome, Von Hippel-Lindau syndrome (VHL) (Ning et al., 2014).

The authors analysed 34 parent-child pairs who were diagnosed with VHL at Peking University First Hospital in Bejing between 2009 and 2012. They found that 31 out of 34 parent-child pairs showed earlier onset of disease and that, on average, disease onset was 16.8 years earlier in the younger generation. This is similar to the results of the HLRCC study, which found that children were diagnosed with renal cell carcinoma roughly 18.6 years earlier than their affected parent.

In order to investigate the cause of the genetic anticipation seen in these families, the authors analysed telomere length, as telomere shortening has been found to cause genetic anticipation in other genetic diseases (Martinez-Delgado et al., 2011). DNA was available from 29 VHL patients, corresponding to 10 of the parent-child pairs, and 9 additional patients. 23 of the 29 patients showed a shorter than average telomere length compared with 325 healthy control samples. Furthermore, in all 10 parent-child pairs, relative telomere length was shorter in the younger generation. All of these families showed earlier age of disease onset in the younger generation, suggesting that shortened telomere length is associated with genetic anticipation in VHL.

In order to conclusively define the role of telomere shortening in VHL, it would be interesting to measure telomere length in those VHL families that do not show genetic anticipation. If no telomere shortening was seen in these families, this would strengthen the hypothesis that telomere shortening causes genetic anticipation in families with VHL. However, this would not explain why some VHL families get telomere shortening and subsequently show genetic anticipation, and other families do not. Alternatively, it is possible that the VHL protein is required to elongate telomeres during embryonic development, and that all people with VHL tend have shortened telomeres. As telomere length lies on a spectrum, it could be that telomere length must fall below a certain threshold before genetic anticipation between generations becomes evident.

This study does not rule out ascertainment bias, where subsequent generations are simply diagnosed at a younger age due to higher awareness of the disease and better diagnostic technology, rather than because they are truly developing symptoms earlier. Furthermore, similarly to the HLRCC study, it only analyses a small number of families from the same population, and does not rule out birth cohort or environmental effects that might cause the younger generation to develop symptoms at a younger age.

Thus more data are required in order to determine how common genetic anticipation is in VHL, HLRCC and other related syndromes like BHD, and what the underlying mechanism is. Indeed, The Cancer in our Genes International Databank for hereditary kidney cancers may be able to identify families showing genetic anticipation, allowing further research into this phenomenon.